Bernhard Heimbach

Applying Automated MR-Based Diagnostic Methods to the Memory Clinic: A Prospective Study.

Abstract Several studies have demonstrated that fully automated pattern recognition methods applied to structural magnetic resonance imaging (MRI) aid in the diagnosis of dementia, but these conclusions are based on highly preselected samples that significantly differ from that seen in a dementia clinic. At a single dementia clinic, we evaluated the ability of a linear support vector machine trained with completely unrelated data to differentiate between Alzheimer’s disease (AD), frontotemporal dementia (FTD), Lewy body dementia, and healthy aging based on 3D-T1 weighted MRI data sets. Furthermore, we predicted progression to AD in subjects with mild cognitive impairment (MCI) at baseline and automatically quantified white matter hyperintensities from FLAIR-images. Separating additionally recruited healthy elderly from those with dementia was accurate with an area under the curve (AUC) of 0.97 (according to Fig. 4). Multi-class separation of patients with either AD or FTD from other included groups was good on the training set (AUC >  0.9) but substantially less accurate (AUC = 0.76 for AD, AUC = 0.78 for FTD) on 134 cases from the local clinic. Longitudinal data from 28 cases with MCI at baseline and appropriate follow-up data were available. The computer tool discriminated progressive from stable MCI with AUC = 0.73, compared to AUC = 0.80 for the training set. A relatively low accuracy by clinicians (AUC = 0.81) illustrates the difficulties of predicting conversion in this heterogeneous cohort. This first application of a MRI-based pattern recognition method to a routine sample demonstrates feasibility, but also illustrates that automated multi-class differential diagnoses have to be the focus of future methodological developments and application studies

Asymmetries of amyloid-β burden and neuronal dysfunction are positively correlated in Alzheimer's disease.

Clinical Alzheimers disease affects both cerebral hemispheres to a similar degree in clinically typical cases. However, in atypical variants like logopenic progressive aphasia, neurodegeneration often presents asymmetrically. Yet, no in vivo imaging study has investigated whether lateralized neurodegeneration corresponds to lateralized amyloid-β burden. Therefore, using combined (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography, we explored whether asymmetric amyloid-β deposition in Alzheimers disease is associated with asymmetric hypometabolism and clinical symptoms. From our database of patients who underwent positron emission tomography with both (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose (n = 132), we included all amyloid-positive patients with prodromal or mild-to-moderate Alzheimers disease (n = 69). The relationship between (11)C-Pittsburgh compound B binding potential and (18)F-fluorodeoxyglucose uptake was assessed in atlas-based regions of interest covering the entire cerebral cortex. Lateralizations of amyloid-β and hypometabolism were tested for associations with each other and with type and severity of cognitive symptoms. Positive correlations between asymmetries of Pittsburgh compound B binding potential and hypometabolism were detected in 6 of 25 regions (angular gyrus, middle frontal gyrus, middle occipital gyrus, superior parietal gyrus, inferior and middle temporal gyrus), i.e. hypometabolism was more pronounced on the side of greater amyloid-β deposition (range: r = 0.41 to 0.53, all P < 0.001). Stronger leftward asymmetry of amyloid-β deposition was associated with more severe language impairment (P < 0.05), and stronger rightward asymmetry with more severe visuospatial impairment (at trend level, P = 0.073). Similarly, patients with predominance of language deficits showed more left-lateralized amyloid-β burden and hypometabolism than patients with predominant visuospatial impairment and vice versa in several cortical regions. Associations between amyloid-β deposition and hypometabolism or cognitive impairment were predominantly observed in brain regions with high amyloid-β load. The relationship between asymmetries of amyloid-β deposition and hypometabolism in cortical regions with high amyloid-β load is in line with the detrimental effect of amyloid-β burden on neuronal function. Asymmetries were also concordant with lateralized cognitive symptoms, indicating their clinical relevance.

Invasive brain-machine interfaces: a survey of paralyzed patients' attitudes, knowledge and methods of information retrieval.

OBJECTIVE Brain-machine interfaces (BMI) are an emerging therapeutic option that can allow paralyzed patients to gain control over assistive technology devices (ATDs). BMI approaches can be broadly classified into invasive (based on intracranially implanted electrodes) and noninvasive (based on skin electrodes or extracorporeal sensors). Invasive BMIs have a favorable signal-to-noise ratio, and thus allow for the extraction of more information than noninvasive BMIs, but they are also associated with the risks related to neurosurgical device implantation. Current noninvasive BMI approaches are typically concerned, among other issues, with long setup times and/or intensive training. Recent studies have investigated the attitudes of paralyzed patients eligible for BMIs, particularly patients affected by amyotrophic lateral sclerosis (ALS). These studies indicate that paralyzed patients are indeed interested in BMIs. Little is known, however, about the degree of knowledge among paralyzed patients concerning BMI approaches or about how patients retrieve information on ATDs. Furthermore, it is not yet clear if paralyzed patients would accept intracranial implantation of BMI electrodes with the premise of decoding improvements, and what the attitudes of a broader range of patients with diseases such as stroke or spinal cord injury are towards this new kind of treatment. APPROACH Using a questionnaire, we surveyed 131 paralyzed patients for their opinions on invasive BMIs and their attitude toward invasive BMI treatment options. MAIN RESULTS The majority of the patients knew about and had a positive attitude toward invasive BMI approaches. The group of ALS patients was especially open to the concept of BMIs. The acceptance of invasive BMI technology depended on the improvements expected from the technology. Furthermore, the survey revealed that for paralyzed patients, the Internet is an important source of information on ATDs. SIGNIFICANCE Websites tailored to prospective BMI users should be further developed to provide reliable information to patients, and also to help to link prospective BMI users with researchers involved in the development of BMI technology.

Contribution of the Cholinergic System to Verbal Memory Performance in Mild Cognitive Impairment

Acetylcholine is critically involved in modulating learning and memory function, which both decline in neurodegeneration. It remains unclear to what extent structural and functional changes in the cholinergic system contribute to episodic memory dysfunction in mild cognitive impairment (MCI), in addition to hippocampal degeneration. A better understanding is critical, given that the cholinergic system is the main target of current symptomatic treatment in mild to moderate Alzheimer’s disease. We simultaneously assessed the structural and functional integrity of the cholinergic system in 20 patients with MCI and 20 matched healthy controls and examined their effect on verbal episodic memory via multivariate regression analyses. Mediating effects of either cholinergic function or hippocampal volume on the relationship between cholinergic structure and episodic memory were computed. In MCI, a less intact structure and function of the cholinergic system was found. A smaller cholinergic structure was significantly correlated with a functionally more active cholinergic system in patients, but not in controls. This association was not modulated by age or disease severity, arguing against compensational processes. Further analyses indicated that neither functional nor structural changes in the cholinergic system influence verbal episodic memory at the MCI stage. In fact, those associations were fully mediated by hippocampal volume. Although the cholinergic system is structurally and functionally altered in MCI, episodic memory dysfunction results primarily from hippocampal neurodegeneration, which may explain the inefficiency of cholinergic treatment at this disease stage.

No difference in paired associative stimulation induced cortical neuroplasticity between patients with mild cognitive impairment and elderly controls.

OBJECTIVE Paired associative stimulation (PAS) is a widely used transcranial magnetic stimulation (TMS) paradigm to induce synaptic long-term potentiation (LTP)-like plasticity in the intact human brain. The PAS effect is reduced in Alzheimers dementia (AD) but has not yet been assessed in patients with mild cognitive impairment (MCI). METHODS PAS was assessed in a group of 24 MCI patients and 24 elderly controls. MCI patients were further stratified by their cognitive profile as well as hippocampal atrophy and Apolipoprotein E (ApoE) genotype. RESULTS There was no difference in PAS effects between MCI patients and healthy controls. MCI patients tended to show a higher response rate and an average PAS effect. PAS effects were not correlated with markers of disease severity or ApoE genotype but were more pronounced in individuals with shorter sleep duration and in MCI subjects with higher ratings of subjective alertness. CONCLUSIONS Contrary to our initial hypothesis, there was no clear difference in PAS between MCI patients and healthy controls. SIGNIFICANCE Our results argue against a continuous reduction of LTP-like plasticity along the spectrum of clinical MCI when stratified by MCI-subtype, APOE genotype or hippocampus atrophy.

Category and design fluency in mild cognitive impairment: Performance, strategy use, and neural correlates.

The exploration and retrieval of words during category fluency involves different strategies to improve or maintain performance. Deficits in that task, which are common in patients with amnestic mild cognitive impairment (aMCI), mirror either impaired semantic memory or dysfunctional executive control mechanisms. Relating category fluency to tasks that place greater demands on either semantic knowledge or executive functions might help to determine the underlying cognitive process. The aims of this study were to compare performance and strategy use of 20 patients with aMCI to 30 healthy elderly controls (HC) and to identify the dominant component (either executive or semantic) for better task performance in category fluency. Thus, the relationship between category fluency, design fluency and naming was examined. As fluency tasks have been associated with the superior frontal gyrus (SFG), the inferior frontal gyrus (IFG), and the temporal pole, we further explored the relationship between gray matter volume in these areas and both performance and strategy use. Patients with aMCI showed significantly lower performance and significantly less strategy use during fluency tasks compared to HC. However, both groups equally improved their performance when repeatedly confronted with the same task. In aMCI, performance during category fluency was significantly predicted by design fluency performance, while in HC, it was significantly predicted by naming performance. In HC, volume of the SFG significantly predicted both category and design fluency performance, and strategy use during design fluency. In aMCI, the SFG and the IFG predicted performance during both category and design fluency. The IFG significantly predicted strategy use during category fluency in both groups. The reduced category fluency performance in aMCI seems to be primarily due to dysfunctional executive control mechanisms rather than impaired semantic knowledge. This finding is directly relevant to patients in the different stages of Alzheimers disease as it links the known semantic fluency deficit in this population to executive functions. Although patients with aMCI are impaired in both performance and strategy use compared to HC, they are able to increase performance over time. However, only HC were able to significantly improve the utilization of fluency strategies in both category and design fluency over time. HC seem to rely more heavily on the SFG during fluency tasks, while in patients with aMCI additional frontal brain areas are involved, possibly reflecting compensational processes.

Voxel-wise deviations from healthy aging for the detection of region-specific atrophy

The identification of pathological atrophy in MRI scans requires specialized training, which is scarce outside dedicated centers. We sought to investigate the clinical usefulness of computer-generated representations of local grey matter (GM) loss or increased volume of cerebral fluids (CSF) as normalized deviations (z-scores) from healthy aging to either aid human visual readings or directly detect pathological atrophy. Two experienced neuroradiologists rated atrophy in 30 patients with Alzheimers disease (AD), 30 patients with frontotemporal dementia (FTD), 30 with dementia due to Lewy-body disease (LBD) and 30 healthy controls (HC) on a three-point scale in 10 anatomical regions as reference gold standard. Seven raters, varying in their experience with MRI diagnostics rated all cases on the same scale once with and once without computer-generated volume deviation maps that were overlaid on anatomical slices. In addition, we investigated the predictive value of the computer generated deviation maps on their own for the detection of atrophy as identified by the gold standard raters. Inter and intra-rater agreements of the two gold standard raters were substantial (Cohens kappa κ > 0.62). The intra-rater agreement of the other raters ranged from fair (κ = 0.37) to substantial (κ = 0.72) and improved on average by 0.13 (0.57 < κ < 0.87) when volume deviation maps were displayed. The seven other raters showed good agreement with the gold standard in regions including the hippocampus but agreement was substantially lower in e.g. the parietal cortex and did not improve with the display of atrophy scores. Rating speed increased over the course of the study and irrespective of the presentation of voxel-wise deviations. Automatically detected large deviations of local volume were consistently associated with gold standard atrophy reading as shown by an area under the receiver operator characteristic of up to 0.95 for the hippocampus region. When applying these test characteristics to prevalences typically found in a memory clinic, we observed a positive or negative predictive value close to or above 0.9 in the hippocampus for almost all of the expected cases. The volume deviation maps derived from CSF volume increase were generally better in detecting atrophy. Our study demonstrates an agreement of visual ratings among non-experts not further increased by displaying, region-specific deviations of volume. The high predictive value of computer generated local deviations independent from human interaction and the consistent advantages of CSF-over GM-based estimations should be considered in the development of diagnostic tools and indicate clinical utility well beyond aiding visual assessments.

REGIO-GERIATRIE — multiprofessionell koordiniert versorgt

ZusammenfassungZur Optimierung einer vernetzten geriatrischen Versorgung könnte eine multiprofessionelle REGIO-GERIATRIE-Leitlinie folgende Themen präzisieren und zu deren Umsetzung in der regionalen Versorgung beitragen: Empfehlung evidenzbasierter Maßnahmen für Fortbildungen zu geriatrischen Kernthemen.Sensibilisierung aller regionalen geriatrischen Akteure für Patienten mit Rehabilitationsindikation und erhöhtem Risiko für fragmentierte Versorgung.Versorgungsplanung und Case-Management für diese Hochrisikopatienten durch eine spezialisierte geriatrische Ambulanz.

Reply to "Motor cortex plasticity in subjects with mild cognitive impairment".

Letter to the Editor Reply to “Motor cortex plasticity in subjects with mild cognitive impairment” Jacob Lahr, Jessica Peter, Lora Minkova, Eliza Lauer, Janine Reis, Bernhard Heimbach, Michael Hüll, Claus Normann, Christoph Nissen, Stefan Klöppel PII: S1388-2457(16)00113-9 DOI: http://dx.doi.org/10.1016/j.clinph.2016.03.019 Reference: CLINPH 2007788 To appear in: Clinical Neurophysiology Accepted Date: 18 March 2016